N,N‘-Bisbenzylidenebenzene-1,4-diamines andN,N‘-Bisbenzylidenenaphthalene-1,4-diamines as Sirtuin Type 2 (SIRT2) Inhibitors

Abstract

A series of N,N'-bisbenzylidenebenzene-1,4-diamine and N,N'-bisbenzylidenenaphthalene-1,4-diamine derivatives were synthesized as inhibitors for human sirtuin type 2 (SIRT2). The design of the new compounds was based on two earlier reported hits from molecular modeling and virtual screening. The most potent compound was N,N'-bis(2-hydroxybenzylidene)benzene-1,4-diamine, which was equipotent with the most potent hit compound and well-known SIRT2 inhibitor sirtinol.

Chemistry of acetyl transfer by histone modifying enzymes: structure, mechanism and implications for effector design

“…To date, several sirtuin effectors have been described including the inhibitors, sertinol (Kiviranta et al, 2006), splitomicin (Posakony et al, 2004) and a group of indole analogues and the activator resveratrol (Biel et al, 2005). The resveratrol activator has received much attention because of its many reported health benefits including its use as a chemotherapeutic agent (Manson et al, 2005).…”

Computer- and structure-based lead design for epigenetic targets

“…Using the same approach Poso et al performed further VS on other compound libraries. [79][80][81] Several moderately active inhibitors could be identified from the Leadquest and Maybridge compound collections.…”

NAD+-dependent histone deacetylases (sirtuins) as novel therapeutic targets

“…Combination of in-silico methodologies and biochemical in vivo assays resulted in the identification of further SIRT2 inhibitors with diverse scaffolds 96,119,120 with moderate potencies, for example compound 21 (see Fig. 13).…”

“…Using the same approach Poso et al performed further virtual screening campaigns on other compound libraries. 119,120,122 Several moderately active inhibitors could be identified from the Leadquest and Maybridge compound collections.…”